Fibroblast Growth factor 18 (FGF-18) is a member of the Fibroblast Growth Factor (FGF) family of proteins, closely related to FGF-8 and FGF-17. Members of the FGF family are characterized by heparin binding domains. Such a putative heparin-binding domain has been identified for FGF-18. It is postulated that receptor-mediated signalling is initiated upon binding of FGF ligand complexed with cell-surface heparin sulfate proteoglycans.
It has been shown that FGF-18 is a proliferative agent for chondrocytes and osteoblasts (Ellsworth et al., 2002, Osteoarthritis and Cartilage, 10: 308-320; Shimoaka et al., 2002, J. Bio. Chem. 277(9):7493-7500). FGF-18 has been proposed for the treatment of cartilage disorder such as osteoarthritis and cartilage injury either alone (WO2008/023063) or in combination with hyaluronic acid (WO2004/032849).
Pharmaceutical compositions comprising an FGF polypeptide are known from the art. WO00/21548 discloses pharmaceutical compositions comprising a recombinant FGF in combination with a pharmaceutically acceptable carrier or diluent. Examples of suitable carriers or diluents for injectable solutions include water or isotonic saline solutions.
WO2008/121563 is related to pharmaceutical formulations comprising an FGF-21 compound prepared in a unit dosage injectable form together with a pharmaceutically acceptable carrier. Suitable carrier might be, among others, a sugar, a buffer and/or a surfactant.
WO92/01442 discloses a lyophilized composition comprising a FGF, a pharmaceutically acceptable bulking agent and either i) an alkali metal salt of cellulose or ii) a combination of polyoxyethylene sorbitan fatty acid ester with cysteine. The components of i) and ii) allow the FGF composition to be stabilized.
WO01/39788 describes pharmaceutical compositions comprising an FGF-18 compound together with a cytotoxin, in a mixture with a pharmaceutically acceptable carrier, e.g. phosphate-buffered saline.
WO2008/023063 discloses formulations comprising an FGF-18 compound together with at least one pharmaceutically acceptable carrier, excipients, or the like. As an example, it discloses a formulation for injection comprising FGF-18 in vehicles such as saline, dextrose solution, serum albumin and Ringer's solution.
When preparing a pharmaceutical composition comprising a bioactive protein, said composition must be formulated in such a way that the activity of the protein is maintained for an appropriate period of time. A loss in activity/stability of the protein may result from chemical or physical instabilities of the protein notably due to denaturation, aggregation or oxidation. The resulting products may thus be pharmaceutically unacceptable. Although the use of excipient(s) is known to increase the stability of a given protein, the stabilizing effects of these excipients is highly dependent of the nature of the excipients and of the bioactive protein itself.
There remains a need for further formulations containing FGF-18 as an active ingredient, wherein said formulations are stable for an appropriate period of time and suitable for use in injection, preferably for intraarticular injection. Said formulations could be useful for administration in the treatment of a cartilage disorder in a patient, such as osteoarthritis or cartilage injury.